雌激素受体ER是人类乳腺癌最重要的治疗靶点及预后指标。雌激素受体下调剂（SERD） 选择性作用于ERα，抑制其调控的下游转录或相关的信号通路。已有SERD通过泛素酶降解ERα蛋白，并不影响ERα基因转录。来源于海洋真菌的6-epi-ophiobolin G (6G)，可以同时在ERα的基因转录和蛋白水平下调ERα, 为一种新颖的ERα 下调方式。确认这种作用方式并阐明其机制对于海洋真菌来源的天然产物药物开发具有重要意义。本项目拟通过在蛋白水平确认6G与ERα 的结合及mRNA水平转录的抑制, 明确这种作用方式；通过考察泛素化系统及ERα 的蛋白稳定性解释其蛋白下调机制；分析其RNA下调是由于降解还是由于合成减少, 解释其转录抑制机理；进而通过转录组、细胞凋亡分析等考察这种下调对下游基因及信号通路的影响；并比较6G与已有SERD单独及联合用药的效果，为新型海洋来源SERD的应用奠定基础。

Estrogen Receptor (ER) is the most important indicator for breast cancer treatment and prognosis. Selective Estrogen Receptor Degradator (SERD) selectively down regulates ERα by a proteasomal degradation mechanism, and not effects the mRNA level of ERα gene expression. Compound 6-epi-ophiobolin G （6G） is produced by a marine fungus and could downregulate both the protein and mRNA level of ERα, which could be a novel mechanism of SERD. Clarify this mechanism is meaningful for developing novel SERD from marine origin. In this proposal, we will confirm the binding of 6G with ERα and whether it consequently degraded by the proteosome via ubiquitination, then we will confirm the decrease of mRNA level and check whether it is caused by down regulating of the de novo synthesis or degradation of mRNA. Furthermore, we will investigate the consequence of this downregulation on the downstream genes expression and the signal pathways modulated by ER, and comparing the single and synergistic growth inhibition effect of 6G with the known SERDs, which will pave the way for the application of novel marine origin SERD.